The present invention relates to an improved process for the synthesis of .alpha.-L-aspartyl-L-phenylalanine methyl ester (.alpha.-APM). ##STR1## .alpha.-APM, first reported in 1969 by Mazur et al., J. Amer. Chem. Soc., 91, 2684 (1969), is an artificial sweetener approximately two hundred times as sweet as sucrose. Since its discovery much effort has been directed toward an efficient synthesis.
Selective formation of a peptide bond in the .alpha.-position of the L-aspartic acid moiety poses a challenge to the synthesis of .alpha.-L-aspartyl-L-phenylalanine methyl ester. It has been shown that the ring opening reaction of N-substituted L-aspartic anhydride with L-phenylalanine or its methyl ester gives a mixture of .alpha. and .beta. adducts, with a predominance of the .alpha.-isomer. Unfortunately, a separation/recovery step is necessary. ##STR2##
Alternately, several regioselective routes to the .alpha.-APM have also been reported by either enzymatic or chemical methods. For example, the approach by Vinick et al., Tet. Letter., 1315 (1982), involves the coupling of L-phenylalanine methyl ester and L-aspartic acid N-thiocarboxyanhydride which was prepared from L-aspartic acid. ##STR3## Unfortunately, regioselective routes to the .alpha.-dipeptide methyl ester reported heretofore are generally impractical. For example, preparation of .alpha.-APM from L-phenylalanine methyl ester and L-aspartic acid N-thiocarboxyanhydride as described above suffers from the disadvantage of using sulfur reactants which normally impart an unpleasant odor to the .alpha.-APM product. This odor is undesirable in view of the intended use of .alpha.-APM as a sweetening agent for foodstuffs and beverages.
Accordingly, the overall object of the present invention is to provide an improved regioselective route to .alpha.-APM.